Prostate cancer (PC) is a prominent cause of death in men in the United States (Boring et al., 1993; Wingo et. al., 1997). The development of diagnostic methods for this disease has demonstrated that it is one of the most prevalent of all cancers (Carter and Coffey, 1990). Although prostate cancer is the most common cancer found in United States men, the molecular changes underlying its genesis and progression remain poorly understood (Boring et al., 1993). The cancer statistics for the year 2004 predicts 230,110 new cases and 29,900 deaths from PC (Jemal et al, 2004). Significant advances have been made in the detection of PC over the last decade, which has been largely associated with the widespread use of prostate-specific antigen (PSA) screening. As a result, a dramatic increase in the incidents of PCs have occurred in the late 1980s and early 1990s, followed by a more recent fall in the incidence (Jemal et al, 2004)].
While prostate-specific antigen (PSA) screening has been useful in identifying PC patients in earlier stages of the disease, high PSA levels alone are not sufficient for the diagnosis of PC. In fact, recent evidence suggests that almost 20% of patients with “normal PSA” levels harbor prostate tumors, and a significant number of those are aggressive (Thompson et al, 2004). On the other hand, higher PSA levels are not sufficient proof for PC, as PSA levels rise in response to benign prostatic hyperplasia (BPH) as well as in response to increases in serum testosterone or prostate growth factors (Polascik et al, 1999). Specifically, serum PSA levels do not discriminate between the cases of BPH and PC (Catalona et al, 2000; Naya et al, 2003; Suzuki et al, 2004). This is because PSA protein is produced by normal as well as malignant prostate cells, and is not a cancer-specific protein, and serum PSA levels depend on the size of the prostate as well as serum testosterone levels. Therefore, the PSA test alone is not sufficient for PC diagnosis.
Numerous recent studies have identified several recurring genetic changes in prostate cancer including: allelic loss (Bova. et al., 1993; Macoska et al, 1994; Carter et al, 1990), generalized DNA hypermethylation, (Isaacs et al., 1994), point mutations or deletions of the retinoblastoma (Rb) and p53 genes (Bookstein et al., 1990a; Bookstein et al., 1990b; Isaacs et al., 1991), alterations in the level of certain adhesion molecules (Carter et al., 1990); Morton et al., 1993a; Morton et al., 1993b; Umbas et al., 1992), and aneuploidy and aneusomy of chromosomes (Macoska et al., 1994; Visakorpi et al., 1994; Takahashi et al., 1994; Alcaraz et al., 1994).
Commonly utilized current tests for prostate cancer are digital rectal examination (DRE) and analysis of serum prostate specific antigen (PSA). Although PSA has been widely used as a clinical marker of prostate cancer since 1988 (Partin and Oesterling, 1994), screening programs utilizing PSA alone or in combination with digital rectal examination have not been successful in improving the survival rate for men with prostate cancer (Partin and Oesterling, 1994). While PSA is specific to prostate tissue, it is produced by normal and benign as well as malignant prostatic epithelium, resulting in a high false-positive rate for prostate cancer detection (Partin and Oesterling, 1994).
Another serum marker associated with prostate disease is prostate specific membrane antigen (PSMA) (Horoszewicz et al., 1987; Carter et al., 1996; Murphy et al., 1996). PSMA is a Type II cell membrane protein and has been identified as Folic Acid Hydrolase (FAH) (Carter et al., 1996). Antibodies against PSMA react with both normal prostate tissue and prostate cancer tissue (Horoszewicz et al., 1987). Murphy et al. (1995) used ELISA to detect serum PSMA in advanced prostate cancer. As a serum test, PSMA levels are a relatively poor indicator of prostate cancer. However, PSMA may have utility in certain circumstances. PSMA is expressed in metastatic prostate tumor capillary beds (Silver et al., 1997) and is reported to be more abundant in the blood of metastatic cancer patients (Murphy et al., 1996). PSMA messenger RNA (mRNA) is down-regulated 8-10 fold in the LNCaP prostate cancer cell line after exposure to 5-alpha-dihydroxytestosterone (DHT) (Israeli et al., 1994).
There remains deficiencies in the art with respect to the identification of genes linked with the progression of prostate diseases, the development of diagnostic methods to monitor disease progression, and the development of therapeutics to treat prostate diseases and cancers. The identification of genes that are differentially expressed in prostate diseases would be of considerable importance in the development of a rapid, inexpensive method to diagnose prostate diseases, including cancer. The identified genes would also be useful in therapeutic compositions, or in screening assays for therapeutic compounds.